1. Field of the Invention
The present invention provides certain novel organic compounds which have immunoregulatory properties, rendering these compounds useful in the treatment of hyperimmunity diseases. Moreover, the present invention provides for the immunoregulatory use of certain organic compounds in hyperimmunity diseases.
Among the novel compounds herein and the compounds employed in the novel methods herein as pharmacological agents are cyclized substituted .omega.-carboxymethyl and .omega.-carboxyethyl mono- or dithiocarbanilic acids and cyclized substituted .omega.-carboxymethyl and .omega.-carboxyethyl mono- or dithiocarbamic acids.
Cyclized .omega.-carboxymethyl and .omega.-carboxyethyl mono- or dithiocarbanilic acids have the structural formula: ##STR1## wherein Y is selected from the group consisting of oxygen and sulfur;
a is the integer one or two; and corresponding cyclized .omega.-carboxymethyl and .omega.-carboxyethyl mono- or dithiocarbamic acids are compounds of the structural formula: ##STR2## wherein Y and a are as defined above. PA1 R.sub.2 is selected from the group consisting of hydrogen and acylamino with acyl of from one to four carbon atoms, inclusive; PA1 n.sub.1 is an integer of from one to three; PA1 n.sub.2 is an integer of from one to five; PA1 n.sub.3 is an integer of from three to five; PA1 Y is selected from the group consisting of oxygen and sulfur. PA1 Y is selected from the group consisting of oxygen and sulfur; PA1 n.sub.1 is an integer of from one to three; and PA1 a is the integer one or two; ##STR9## wherein R.sub.6 is selected from the group consisting of hydrogen and acylamino of from one to four carbon atoms, inclusive; PA1 R" is selected from the group consisting of chloro, bromo, fluoro and trifluoromethyl; PA1 Y is defined as above; PA1 n.sub.2 is an integer of from one to five; ##STR10## wherein R.sub.7 and R.sub.8 are the same or different and are selected from the group consisting of hydrogen, alkyl of from one to four carbon atoms, inclusive, carboxyalkyl and pharmaceutically acceptable salts thereof; such that when R.sub.7 and R.sub.8 are different one of the selection is hydrogen; PA1 R" is selected from the group consisting essentially of bromo, chloro, fluoro and trifluoromethyl; PA1 Y is defined as above; and PA1 n.sub.2 is an integer of from one to five; and ##STR11## R" is selected from the group consisting of fluoro, chloro, bromo and trifluoromethyl; PA1 n.sub.3 is an integer of from three to five, and PA1 Y is as defined above; PA1 n.sub.2 is an integer of from one to five; and PA1 Y is as defined above;
Compounds of the above structures are known as thiazines and thiazolines which may be rhodanines.
2. The Prior Art
Certain thiazines and rhodanines are known in the art as useful for a wide variety of purposes. Compounds within these classes are structurally derived from corresponding intermediates which are prepared, for example, by reactions between .omega.-mercaptoalkylcarboxy acids and isocyanates or isothiocyanates. Subsequent dehydration results in internal cyclization of the intermediates with yields of thiazines and rhodanines. Dehydration is accomplished with addition of acetic anhydride containing a few drops of strong acid. Methods to prepare certain intermediates and the cyclized derivatives of the present invention are well known.
See, for example, Garroway, J. L., J. Chem. Soc. 1961:3733-5 which describes .omega.-carboxyalkyl dithiocarbanilic acids as precursors for corresponding cyclic lactams, i.e. rhodanines and thiazine analogs. For production of rhodanine or thiazine analogs from corresponding .omega.-carboxyalkyl dithiocarbanilic acid precursors see also U.S. Pat. Nos. 3,781,434; 3,732,216 and 3,816,627; Brown, F. C., et al., J.A.C.S. 78:384 (1956); Werbel, L. M., et al., J. Med. Chem. 11 (2):364 (1968) and a Belgian application 862,725, filed July 13, 1978 having Derwent Number 33497A/19 by Yoshitomo Pharm. Ind. KK (also now issued as U.S. Pat. No. 4,169,899).
The United States patents noted above describe the antiarthritic use of two groups of substituted thiazines, including, inter alia, compounds of the formula: ##STR3## wherein according to U.S. Pat. Nos. 3,781,434 and 3,732,216 "A" represents phenyl substituted by a halogen such as chlorine, bromine and fluorine or trifluoromethyl and wherein according to U.S. Pat. No. 3,816,627 "A" represents a heterocyclic moiety, particularly one containing nitrogen. In the Yoshitomo Belgian Application "A" includes an alkylene linkage having one to five carbons between the nitrogen on the thiazine and any other moiety thereon which therefore distinguishes it from the present invention.
The remaining references listed above describe certain rhodanines as anti-fungicidal, anti-bacterial and anti-malarial agents.
W. Hanefeld, Archio Der Pharmazie Vol. 308, (1975) pp, 450-454 describes fungiostatic properties of certain dioxo and thioxo tetrahydro-1,3-thiazines.
Immunoregulatory agents may be either immunosuppressive or immunostimulatory. For the purposes of this invention, the process of immunosuppression is the desired response to a disease or other condition which results from hyperimmunity in the animal or patient. Immunosuppressive use of .omega.-carboxyalkyl and .omega.-(alkoxycarbonyl)alkyl esters of dithiocarbanilic acid and certain arylsubstituted acids related thereto are found in U.S. Pat. No. 4,110,444 and copending Ser. No. 848,433, now abandoned. For a comprehensive review of the use of immunosuppressive agents in the treatment of hyperimmunity diseases, see Camiener, G. W., et al., Progress in Drug Research 16:67 (1972) and Wechter, W. J., et al., Progress in Drug Research 20:573 (1976).
Many known immunosuppressive agents are cytotoxic and are believed in part, if not exclusively, to accomplish the immunosuppressive effects via a cytotoxic mechanism on the immunoactive organs (e.g. bone marrow and thymus) and on the proliferating dynamic primary and secondary lymphold tissue. For example, known antineoplastic agents such as cyclophosphamide, have been used in the treatment of arthritis. See Skinner, M. D., et al., Rheumatology 5:1 (1974).
Finally, anthelmintics such as niridazole have been employed immunosuppressively to control allograft rejection; while another anthelmintic, levamisole, is apparently a non-specific stimulator of the immune system. See Daniels, J. D., et al., J. Immuno 115:1414 (1975) and Renorex, G., et al., J. Immun. 109:761 (1972).